| A variety of human cancers including breast, liver, colorectal, lung, and prostate cancers have loss of heterozygosity (LOH) of the igf2r gene locus on chromosome 6q26-27. These data suggest that the IGF-IIR may be a tumor suppressor. Our findings demonstrate that loss of expression of the IGF-IIR in both murine L and MMSV fibroblasts promotes growth. In murine L cells, loss of IGF-IIR sustains high levels of IGF-II mitogen, which binds and activates both the IGF-I and insulin receptors to increase the duration and extent of the intracellular growth signal, phospho-IRS-1. IGF-IIR deficient MMSV clones grow more rapidly than MMSV clones engineered to over-express the IGF-IIR under serum-free conditions when cells are initially primed with 10% serum. IGF-II cannot substitute for serum during the initial priming step and TGF-β does not inhibit growth of IGF-IIR deficient MMSV cells to levels of IGF-IIR positive cells. Thus, the results suggest factors other than IGF-II or TGF-β either in serum or produced by the cells mediate the growth of IGF-IIR deficient MMSV cells. To evaluate the invasive potential of these murine cells, an in vitro invasion assay was performed. Murine L cells rapidly invade through Matrigel. Interestingly, loss of expression of the IGF-IIR in L cells decreases their ability to degrade Matrigel compared to L cells that over-express the IGF-IIR. Conversely, MMSV cells are poor invaders of Matrigel and loss of IGF-IIR expression in these cells has little effect on their ability to degrade to Matrigel. The invasiveness of IGF-IIR positive L cells is inhibited by 30% in the presence of CA-O74Me, an intracellular inhibitor of cathepsin B. These results suggest that an increase in levels of intracellular active lysosomal enzymes such as cathepsin B is partly responsible for the increase in invasion of tumorigenic murine L cells that express the IGF-IIR.{09}These results suggest that loss of IGF-IIR expression can stimulate the growth of tumor cells but could decrease their ability to degrade extracellular matrix for some cell types. |
